The long-term objective of this proposal is to design and develop novel strategies to inhibit/reduce PCSK9 action. This is a potential powerful new therapeutic target to regulate LDL cholesterol and reduce the burden of cardiovascular disease. PCSK9 (Proprotein convertase subtilisin/kexin type 9) is a newly discovered gene that has a profound effect on LDL cholesterol levels by binding to LDL receptor and acts as a chaperon, mediates LDL receptor to lysosome for degradation. Studies in Humans demonstrated that total PCSK9 deficiency had very low LDL cholesterol (14-16 mg/dl) with no adverse clinical consequences. Thus, PCSK9 would be an excellent target for the treatment of hypercholesterolemia. Moreover, it has been shown that statins increase PCSK9 transcription, resulting in higher plasma PCSK9 levels. Then, a combination treatment of statins and PCSK9 inhibitor(s) would provide a better therapy to reduce LDL cholesterol. In this application, we propose to use an active immunotherapy strategy by generating a vaccine that stimulates the immune system against PCSK9. Proteins are unique bio-molecules, they unfold and refold, generate a mixture of diverse conformational isomers. We developed a technique of disulfide scrambling permits reversible conversion between the native and diverse denatured isomers. Our preliminary results have shown that these isomers induced immunogenicity towards native protein and decreased plasma cholesterol levels. This is a novel approach to use disulfide scrambling to generate conformational isomers of Pcsk9 (X- Pcsk9) to induce immunogenicity towards native Pcsk9. This process will block the interaction of PCSK9 and LDL receptor to decrease LDL cholesterol for the treatment of hypercholesterolemia. Moreover, Vaccine for atherosclerosis towards oxidized LDL or apolipoprotein B peptide has shown some success. Thus, the proposal of developing vaccine against PCSK9 to regulate LDL cholesterol is an exciting and feasible approach In this application, we will generate and produce a panel of X-Pcsk9 isomers vaccines, which will cross- react with native Pcsk9. We propose to evaluate the potency of these vaccines on decreasing cholesterol levels as well as modulating atherosclerosis development in vivo. In summary, this study will provide novel therapeutic treatment for decreasing LDL levels and reducing the burden of cardiovascular disease.